Original articles
Valeria Marrocco, Tuan Tran, Siying Zhu, Seung Hyuk Choi, Ana M. Gamo, Sijia Li, Qiangwei Fu, Marta Diez Cunado, Jason Roland, Mitch Hull, Van Nguyen-Tran, Sean Joseph, Arnab K. Chatterjee, Nikki Rogers, Matthew S. Tremblay, Weijun Shen. A small molecule UPR modulator for diabetes identified by high throughput screening[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3983-3993

A small molecule UPR modulator for diabetes identified by high throughput screening
Valeria Marrocco, Tuan Tran, Siying Zhu, Seung Hyuk Choi, Ana M. Gamo, Sijia Li, Qiangwei Fu, Marta Diez Cunado, Jason Roland, Mitch Hull, Van Nguyen-Tran, Sean Joseph, Arnab K. Chatterjee, Nikki Rogers, Matthew S. Tremblay, Weijun Shen
Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA
Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models. Using asialoglycoprotein receptor 1 (ASGR) fused with Cypridina luciferase (CLuc) as reporter assay for folding capacity, we have screened a million small molecule library and identified APC655 as a potent activator of protein folding, that appears to act by promoting chaperone expression. Furthermore, APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines. APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient (ob/ob) mouse model. These results demonstrate a successful uHTS campaign that identified a modulator of UPR, which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.
Key words:    β cells    Unfolded protein response    Small molecules    Protein folding    Endoplasmic reticulum    Chaperones    Cell signaling    Diabetes    ER stress    Liver    Pancreas    Metabolic diseases   
Received: 2021-01-26     Revised: 2021-03-25
DOI: 10.1016/j.apsb.2021.05.018
Funds: The work was supported by the Juvenile Diabetes Research Foundation (JDRF) [3-PAR-2016-241-I-X, US]. We thank Gökhan Hotamisligil for providing the reporter cell lines and Patricia Kilian, Andrew Rakeman, Peter Lomedico, and Frank Martin (JDRF, USA) for helpful discussions.
Corresponding author: Weijun Shen,E-mail:wshen@scripps.edu     Email:wshen@scripps.edu
Author description:
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Valeria Marrocco
Tuan Tran
Siying Zhu
Seung Hyuk Choi
Ana M. Gamo
Sijia Li
Qiangwei Fu
Marta Diez Cunado
Jason Roland
Mitch Hull
Van Nguyen-Tran
Sean Joseph
Arnab K. Chatterjee
Nikki Rogers
Matthew S. Tremblay
Weijun Shen

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